title: Posttranslational modification of HLA-DQ binding islet autoantigens in type 1 diabetes.
abstract: Posttranslational modification (PTM) of islet autoantigens can cause lack of central tolerance in type 1 diabetes (T1D). Tissue transglutaminase (tTG), involved in PTM of gluten antigens in celiac disease, creates negatively charged peptides favored by T1D-predisposing HLA-DQ molecules, offering an attractive candidate modifying islet autoantigens in T1D. The highly predisposing HLA-DQ8cis/trans molecules share preferences for negatively charged peptides, as well as distinct peptide-binding characteristics that distinguish their peptide-binding repertoire. We screened islet autoantigens with the tTG substrate motif for candidate-modified epitopes binding to HLA-DQ8cis/trans and identified 31 candidate islet epitopes. Deamidation was confirmed for 28 peptides (90%). Two of these epitopes preferentially bound to HLA-DQ8cis and six to HLA-DQ8trans upon deamidation, whereas all other peptides bound equally to HLA-DQ8cis/trans. HLA-DQ8cis-restricted T cells from a new-onset T1D patient could only be generated against a deamidated proinsulin peptide, but cross-reacted with native proinsulin peptide upon restimulation. The rate of T-cell autoreactivity in recent-onset T1D patients extended from 42% to native insulin to 68% adding responses to modified proinsulin, versus 20% and 37% respectively, in healthy donors. Most patients responded by interferon-γ, whereas most healthy donors produced interleukin-10 only. Thus, T-cell autoreactivity exists to modified islet epitopes that differs in quality and quantity between patients and healthy donors.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Menno
authors.initials: M
authors.lastname: van Lummel
authors.forename: Gaby
authors.initials: G
authors.lastname: Duinkerken
authors.forename: Peter A
authors.initials: PA
authors.lastname: van Veelen
authors.forename: Arnoud
authors.initials: A
authors.lastname: de Ru
authors.forename: Robert
authors.initials: R
authors.lastname: Cordfunke
authors.forename: Arnaud
authors.initials: A
authors.lastname: Zaldumbide
authors.forename: Iria
authors.initials: I
authors.lastname: Gomez-Touriño
authors.forename: Sefina
authors.initials: S
authors.lastname: Arif
authors.forename: Mark
authors.initials: M
authors.lastname: Peakman
authors.forename: Jan W
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: Bart O
authors.initials: BO
authors.lastname: Roep
mesh_terms: D001324:Autoantigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000939:Epitopes; D005260:Female; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D001324:Autoantigens; D000939:Epitopes; D006683:HLA-DQ Antigens; D016753:Interleukin-10; D007371:Interferon-gamma